Several conserved nuclear RNA binding proteins (sut-1, sut-2, and parn-2) control tau aggregation and toxicity in C. elegans, mice, and human cells. MSUT2 protein normally resides in nuclear speckles, membraneless organelles composed of phase-separated RNAs and RNA-binding proteins that mediate critical steps in mRNA processing including mRNA splicing. We used human pathological tissue and transgenic mice to identify Alzheimer’s disease-specific cellular changes related to nuclear speckles. We observed that nuclear speckle constituent scaffold protein SRRM2 is mislocalized and accumulates in cytoplasmic lesions in AD brain tissue. Furthermore, progression of tauopathy in transgenic mice is accompanied by increasing mislocalization of SRRM2 from the neuronal nucleus to the soma. In AD brain tissue, SRRM2 mislocalization associates with increased severity of pathological tau deposition. These findings suggest potential mechanisms by which pathological tau impacts nuclear speckle function in diverse organisms ranging from C. elegans to mice to humans. Future translational studies aimed at restoring nuclear speckle homeostasis may provide novel candidate therapeutic targets for pharmacological intervention.

中文翻译：

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病理性 tau 驱动异位核散斑支架蛋白 SRRM2 在阿尔茨海默病神经元细胞质中的积累

几种保守的核 RNA 结合蛋白（sut-1、sut-2 和 parn-2）控制线虫、小鼠和人类细胞中的 tau 聚集和毒性。MSUT2 蛋白通常存在于核斑点、由相分离的 RNA 和 RNA 结合蛋白组成的无膜细胞器中，它们介导 mRNA 加工中的关键步骤，包括 mRNA 剪接。我们使用人类病理组织和转基因小鼠来识别与核斑点相关的阿尔茨海默病特异性细胞变化。我们观察到核散斑成分支架蛋白 SRRM2 定位错误并在 AD 脑组织的细胞质病变中积累。此外，转基因小鼠中 tau 病变的进展伴随着 SRRM2 从神经元核到体细胞的错误定位增加。在 AD 脑组织中，SRRM2 错误定位与病理性 tau 沉积的严重程度增加有关。这些发现表明了病理性 tau 影响从秀丽隐杆线虫到小鼠到人类的多种生物体中的核斑点功能的潜在机制。未来旨在恢复核散斑稳态的转化研究可能为药物干预提供新的候选治疗靶点。